DESCRIPTION: (Applicant's Abstract) Although the cannabinoids have been and continue to be abused by many individuals in our society, their cellular mechanisms of action are not well understood. This lack of understanding has several consequences. First, without information concerning the cellular effects of the cannabinoids, estimates of the potential risks of use of this drug by humans are very difficult to make. Second, the full therapeutic potential of these agents cannot be exploited. Third, the cannabinoids produce a completely unique spectrum of effects so a more thorough understanding of their mechanism of action will provide basic information about brain functioning. A cannabinoid binding site (CB1) that has many of the characteristics of a G protein-coupled receptor has been identified in brain. It is our hypothesis delta 9-tetrahydrocannabinol (THC) and other synthetic cannabimimetics act as inhibitory modulators of neurotransmission as a result of activating the CB1 receptor. In specific, we hypothesize that CB1 activation results in the closure of voltage operated calcium channels. We will use cerebellar granule neurons in primary culture to study this hypothesis. We have three aims in this proposal; first, we will characterize the CB1 receptors of the cerebellum in terms of the efficacy of a variety of CB1 ligands to induce the G coupled state of the receptor and to promote G protein guanine nucleotide exchange. Second, we will determine which G-protein(s) couple to the CB1 receptor in the granule cells. Our third aim is to explore the hypothesis that the cannabinoids, acting through CB1, inhibit voltage-regulated calcium channels in cerebellar granule cells. As part of this aim, we will determine the types of calcium channels or currents involved in the effects of the cannabinoids as well as determine whether this effect is pertussis-toxin sensitive. We will also determine whether the effect of the cannabinoids on calcium is due to inhibition of adenylyl cyclase. It is anticipated that the successful completion of these studies will enhance our understanding of the mechanism of action of the cannabinoids and the neurochemical processes with which they interact in the brain.